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Michel Adamina

Publications and source records attributed to Michel Adamina.

15 recordsLinked to original sources
PubMed2007

Cancer/testis antigen expression and specific cytotoxic T lymphocyte responses in non small cell lung cancer.

Non small cell lung cancers (NSCLC) express cancer/testis antigens (CTA) genes and MAGE-A expression correlates with poor prognosis in squamous cell carcinomas. We addressed cytotoxic T lymphocytes (CTL) responses to HLA class I restricted CTA epitopes in TIL from NSCLC in an unselected group of 33 patients consecutively undergoing surgery. Expression of MAGE-A1, -A2, -A3, -A4, -A10, -A12 and NY-ESO-1 CTA genes was tested by quantitative RT-PCR. Monoclonal antibodies (MAb) recognizing MAGE-A and NY-ESO-1 CTA were used to detect CTA by immunohistochemistry. CD8(+) TIL obtained from tumors upon culture with anti CD3 and anti CD28 mAb and IL-2 were stimulated with autologous mature DC (mDC) and HLA-A*0101 restricted MAGE-A1(161-169) or MAGE-A3(168-176) peptides or HLA-A*0201 restricted MAGE-A4(230-239), MAGE-A10(254-262), NY-ESO-1(157-165) or multi-MAGE-A (YLEYRQVPV) peptides or a recombinant vaccinia virus (rVV) encoding MAGE-A and NY-ESO-1 HLA-A*0201 restricted epitopes and CD80 co-stimulatory molecule. Specificity was assessed by (51)Cr release and multimer staining. At least one CTA gene was expressed in tumors from 15/33 patients. In 10 specimens, at least 4 CTA genes were concomitantly expressed. These data were largely confirmed by immunohistochemistry. TIL were expanded from 26/33 specimens and CTA-specific CTL activity was detectable in 7/26 TIL. In 6, however, specific cytotoxicity was weak, (<40% lysis at a 50:1 E:T ratio) and multimer staining was undetectable. In one case, high (>60% lysis at 50:1 E:T ratio) MAGE-A10(254-262) specific, HLA-A*0201 restricted response was observed. Supportive evidence was provided by corresponding multimer staining. Although CTA genes are frequently expressed in NSCLC, detection of CTL reactivity against CTA epitopes in TIL from nonimmunized NSCLC patients represents a rare event.

Aged↗
PubMed2006

Advanced liposomal vectors as cancer vaccines in melanoma immunotherapy.

Malignant tumors represent a major source of disability and account for more than one of five deaths in Western countries. Among the different cancers, melanoma harbors two distinctive features. First, its has long been recognized as an immunogenic tumor, and second, an unprecedented rise in incidence is currently observed, in face of few therapeutic options. Thus, melanoma represent an ideal target for a cancer immunotherapy program. To date, a number of immunodominant epitopes from tumor associated antigens (TAA) are used as cancer vaccines in clinical trials, in spite of an acknowledged rapid degradation in vivo and low immunogenicity. However, most of the immunotherapy trials reported so far do not achieve consistent clinical results. Hence, there is an urgent need for the development of a carrier system and strong adjuvants suitable for a TAA-based cancer immunotherapy. Liposomes and their further development as virosomes with added adjuvancy may address both these issues. We report here our experience in the tailoring of dedicated advanced liposomal vectors that were developed in the context of an upcoming immunotherapy clinical trial for melanoma.

Cancer Vaccines↗
PubMed2006

Clinical applications of virosomes in cancer immunotherapy.

Cancer immunotherapy is increasingly accepted as a treatment option for advanced stage disease. The identification of tumour-associated antigens in 1991 has prompted the development of antigen-specific immunotherapeutic strategies for a variety of cancers. Many of them result in some immunological responses in cancer patients; however, clinical results were not observed concomitantly with immunological responses; therefore, further improvements in the field of immunotherapy are urgently needed. Virosomes are lipidic envelopes devoid of genetic information, but which retain the antigenic profile and fusogenic properties from their viral origin. Virosomes are versatile antigen carriers and can be engineered to perform various tasks in cancer immunotherapy. Preclinical data have fostered the development of innovative clinical protocols. Hence, immunopotentiating reconstituted influenza virosomes will be assessed in breast and melanoma immunotherapy, and may contribute to the development of clinically effective cancer vaccines and ultimately improve patient outcomes. The objective of this review is to provide an overview of the potential clinical applications of virosomes as innovative and potentially effective reagents in active specific cancer immunotherapy.

Animals↗
PubMed2005

Efficient induction of tumoricidal cytotoxic T lymphocytes by HLA-A0201 restricted, melanoma associated, L(27)Melan-A/MART-1(26-35) peptide encapsulated into virosomes in vitro.

Cancer immunotherapy requires the induction of HLA class I restricted cytotoxic T lymphocytes (CTL) specific for tumor associated antigens (TAA). While a number of TAA have been identified, there is an urgent need for the development of adjuvants capable of stimulating CTL responsiveness. Previously, we reported the capacity of immunopotentiating reconstituted influenza virosomes (IRIV) to enhance CTL responses specific for synthetic peptides simultaneously added to cultures in soluble form. This effect was based on IRIV mediated activation of CD4(+) T cells. Here we investigated the "in vitro" immunogenicity of a novel virosome formulation coupling in a single reagent the adjuvant power of IRIV to the capacity of liposomes to efficiently encapsulate synthetic peptides. As a model epitope we chose L(27)Melan-A/Mart-1(26-35) HLA-A0201 restricted peptide from a melanoma-associated antigen widely used in tumor immunotherapy. The reagent thus developed induced the proliferation of CD4(+) T cells characterized by a T helper 1 cytokine profile and CXCR3 expression. Most importantly, it significantly enhanced the generation of L(27)Melan-A/Mart-1(26-35) specific CTL, as compared to soluble peptides, in particular at low nominal epitope concentrations (<1 microg/ml). These effector cells were able to efficiently kill HBL melanoma cells expressing Melan-A/MART-1 and HLA-A0201. The adjuvant effects observed were also detectable in the absence of CD4(+) T cells. Taken together our results suggest that this highly immunogenic antigenic formulation might qualify for clinical use in active, antigen-specific, melanoma immunotherapy.

Adjuvants, Immunologic↗
PubMed2005

Selective responsiveness to common gamma chain cytokines in peripheral blood-derived cytotoxic T lymphocytes induced by Melan-A/MART-1(27-35)targeted active specific immunotherapy.

We have comparatively evaluated the proliferative response of CTL induced in metastatic melanoma patients upon immunization against Melan-A/MART-1(27-35) tumor associated antigen (TAA) to IL-2, IL-7 or IL-15 cytokines, sharing a receptor common gamma-chain (c gamma-c cytokines). Twenty-eight CTL clones were generated from CD8+ T cells obtained from 3 patients during the contraction phase of immune response following a successful vaccine mediated expansion of specific effectors. All clones were able to kill tumor cell lines expressing HLA-A0201 and Melan-A/MART-1, and displayed phenotypic characteristics of effector/memory (CD45RA-/CCR7-) or CD45RA+/CCR7- effector cells in intermediate to late developmental stage (CD28-/CD276+/-) CTL. Proliferative responses could be elicited or enhanced by IL-2 and IL-15, but not IL-7, in the absence or in the presence of T-cell receptor (TCR) triggering, respectively. Accordingly, only IL-2 and IL-15 were able to promote the survival of the CTL clones under investigation. While all clones expressed high amounts of receptor c gamma-c (CD132), lower, but detectable, expression of IL-7 receptor alpha chain was also observed. CD8+ cells from one of the patients treated were obtained 6 months after the last vaccine boost and were cultured in the presence of Melan-A/MART-1(27-35) and each of the 3 cytokines under investigation. Consistent with data from CTL clones, expansion of Melan-A/MART-1(27-35) tetramer positive cells was only observed in the presence of IL-2 or IL-15 but not IL-7. Instead, when CD8+ cells from the same patient were sampled shortly (14 days) after an additional vaccination only IL-2 was able to promote the expansion of Melan-A/MART-1(27-35) tetramer positive cells. Taken together these data suggest a selective responsiveness of TAA-specific CTL to different c gamma-c cytokines.

Antigens, Neoplasm↗
PubMed2005

Antigen specific active immunotherapy: lessons from the first decade.

Malignant melanoma is a tumour with a steeply rising incidence and scarce therapeutic options once metastatic. Approximately 1200 new cases are reported yearly in Switzerland with roughly 220 deaths/year. An important particularity of melanoma is its immunogenicity, which has long been recognized and investigated using various clinical immunization protocols in the last fifty years. The year 1991, when the first melanoma associated antigen was molecularly characterized, represents a turning point in the quest for a melanoma immunotherapy. This opened the era of antigen specific active immunotherapy. Many clinical centres have developed immunization strategies in an adjuvant setting for the treatment of metastatic melanoma. The molecular characterization of melanoma associated antigens allows a fine monitoring of the elicited immune response. Certain clinical responses to these efforts have been seen and a phase of reflection is now ongoing, with refinements and further sophistication taking place in order to fully realize the potential of antigen specific active immunotherapy. Here we provide an overview of the technologies used and of the progress reported in melanoma immunotherapy since 1991. Furthermore, we propose some research lines in basic and translational research aimed at improving our capacity to induce specific and clinically relevant immune responses against melanoma.

Antigens, Neoplasm↗
PubMed2005

Active antigen-specific immunotherapy of melanoma: from basic science to clinical investigation.

Advanced-stage melanoma here dismal prognosis, and novel therapeutic approaches are urgently required. The possibility of taking advantage of the immune response of patients for its treatment has been an appealing concept for almost a century. Only during the last decade, however, has the molecular identification of tumor-associated antigens (TAAs) offered the possibility of vaccinating patients (e.g., active induction of TAA-specific immune responses). Active antigen-specific immunotherapy (AASIT) is currently being investigated in a number of clinical centers as a treatment option for advanced-stage melanoma. A large number of melanoma TAAs have been molecularly characterized and are being used in vaccination trials in various molecular forms and according to various immunization protocols. Here we provide a short overview on melanoma TAAs, the technologies currently in use to induce specific cytotoxic T-lymphocyte (CTL) responses in vivo, and their monitoring. We also propose a tentative AASIT agenda for the next few years, aiming at improving the capacity to induce and monitor TAA-specific immune responses and to verify their clinical effectiveness.

Antigens, Neoplasm↗
PubMed2005

Intractable abdominal pain following laparoscopic adjustable gastric banding.

A 42-year-old woman presented with intractable crampy abdominal pain continuing for 1 year. The pain worsened after eating and improved when walking. She had undergone laparoscopic adjustable gastric banding 4 years previously, with re-banding 18 months later because of anterior band slippage. The patient underwent numerous examinations, all with normal findings. A scintigraphy finally showed some tracer enrichment in the terminal ileum, which led to the assumption that a Meckel's diverticulum was causing her discomfort. Subsequent diagnostic laparoscopy showed no Meckel's diverticulum but instead displaced tubing, which was wrapped around the mesenteric root. The mesenteric root showed scarred alterations from chronic strangulation. After replacing the tubing from the band the abdominal pain immediately vanished. In retrospect, the contrast study of the gastric band shows unnatural traction of the tubing towards the lower abdomen, allowing suspicion of the intraoperative findings.

Abdominal Pain↗
PubMed2005

Clinical applications of recombinant virus-based cancer immunotherapy.

Cancer immunotherapy looks back over one century of clinical applications. In spite of major advances in the comprehension of oncogenesis and treatment of cancer, malignant tumours remain a leading cause of disability and death worldwide. Since 1991, a breakthrough in immunology allowed the identification of tumour-associated antigens, opening the era of specific immunotherapy. On the other hand, recombinant virus are powerful vectors that are able to express various gene products in vivo, including cytokines and tumour antigens. Therefore, many groups have implemented clinical trials of active specific tumour immunotherapy. Phase I trials have demonstrated favourable safety profiles. However, major tumour responses remain anecdotal in heavily metastatic patients. This review will critically present and discuss the clinical achievements of recombinant virus-based cancer immunotherapy. This paper will attempt to shed some light on the perspectives opened by advanced cancer immunotherapy protocols, review the drawbacks of this approach and the reasons why it is believed that recombinant virus-based cancer immunotherapy may be of relevance in the treatment of human malignancies.

Animals↗
PubMed2004

Influenza virosomes enhance class I restricted CTL induction through CD4+ T cell activation.

Immunopotentiating reconstituted influenza virosomes (IRIV) are one of the few adjuvants currently licensed for human use. While their adjuvant capacity in the induction of humoral responses is clearly documented, few data exist on their effects on T cell immune response. Here we addressed IRIV adjuvance in the induction of HLA class I restricted cytotoxic T lymphocytes (CTL) in vitro. Lymphocyte stimulation with IM(58-66) and IRIV resulted in marked expansion of specific CTL as compared to cultures performed in the presence of either antigen alone or antigen and control liposomes (L). Studies addressing underlying adjuvant mechanisms demonstrated that IRIV activated CD4/CD45RO+ T cells, induced a cytokine profile consistent with T helper 1 (Th1) stimulation and increased the percentage of CD4+ T cells expressing CXCR3. Furthermore, supernatants from IRIV stimulated PBMC cultures promoted dendritic cell maturation. Most importantly, IRIV mediated CTL adjuvance required the presence of live CD4+ T cells. Powerful adjuvant effects of IRIV were also observed in the induction of CTL specific for the melanoma associated Melan-A/MART-1(27-35), HLA-A0201 restricted epitope. Taken together these findings indicate that IRIV are endowed with a high adjuvant capacity for HLA class I restricted CTL induction, largely attributable to their ability to antigenically stimulate CD4+ T cells.

Adjuvants, Immunologic↗
PubMed2004

Hydrolysis of the tumor-associated antigen epitope gp100(280-288) by membrane-associated and soluble enzymes expressed by immature and mature dendritic cells.

The hydrolysis of the tumor-associated HLA-A2.1-restricted gp100(280-288) epitope by in vitro generated immature and mature dendritic cells (iDCs and mDCs) and by soluble supernatants prepared from these same cells, as well as the effect of the hydrolysis on in vitro immunorecognition, was studied by chromatographic and functional analyses. The results obtained indicate that exposure to iDCs induced a very rapid hydrolysis of the model peptide (half life, 62 s), resulting in complete loss of immunorecognition within 60 min. In the presence of mDCs, the hydrolysis kinetics were even faster (half life, 54 s), and the pattern of hydrolysis by-products was different from that observed for iDCs. Gp100(280-288) was also degraded in the presence of cell-free supernatants prepared both from iDCs and mDCS; in this case, degradation kinetics were slower, and the pattern of hydrolysis by-products was different from that observed in the presence of intact cells. The model epitope was degraded to non-immunogenic products by membrane and soluble enzymes expressed both by iDCs and by mDCs within periods of time that appear to be physiologically relevant. Development of antigenic formulations capable of protecting synthetic epitopes from these effects appears to represent a prerequisite for effective immunization procedures.

Amino Acids↗
PubMed2002

Rapid induction of specific cytotoxic T lymphocytes against melanoma-associated antigens by a recombinant vaccinia virus vector expressing multiple immunodominant epitopes and costimulatory molecules in vivo.

A specific cellular immune response directed against a panel of three defined tumor-associated antigen (TAA) epitopes was induced in metastatic melanoma patients by a prime-boost strategy taking advantage of an innovative recombinant vaccinia virus as evaluated by quantitative assessment of cytotoxic T lymphocytes (CTLs) with corresponding specificity. The immunization protocol consisted of the administration of psoralen-UV-treated and replication-incompetent recombinant vaccinia virus encoding the three immunodominant HLA-A*0201-restricted epitopes Melan-A(27-35), gp100(280-288), and tyrosinase(1-9) together with two costimulatory molecules, B7.1 and B7.2, in the context of systemic granulocyte-macrophage colony-stimulating factor (GM-CSF) treatment. Boosts were subsequently applied with corresponding synthetic nonapeptides and GM-CSF. Specific CTL induction was assessed by tetramer staining and CTL precursor (CTLp) frequency evaluation. Within 12 days of injection of the recombinant vector, cytotoxic T cell responses specific for engineered epitopes were detectable in three of three patients. During the vaccination treatment, antigen-specific CTLp frequencies exceeding 1:10,000 peripheral CD8(+) T cells could be observed. Tetramer staining also revealed significant increases in specific CD8(+) T cell numbers. We conclude that active specific antitumor vaccination can raise a concurrent and specific cellular immune response against a panel of molecularly defined antigens, thereby increasing the chance of an immune hit against neoplastic cells with heterogeneous antigen expression. Data from this study emphasize the potency of a recombinant vaccinia virus vector encoding multiple minigenes and costimulatory molecules in the context of exogenously administered GM-CSF. Clinical effectiveness of this immunologically active protocol should therefore be explored in appropriately selected groups of patients.

Antigens, Neoplasm↗
PubMed2002

Cytotoxic T-cell induction in metastatic melanoma patients undergoing recombinant vaccinia virus-based immuno-gene therapy.

In an ongoing phase I/II study, metastatic melanoma patients were treated with a replication-incompetent recombinant vaccinia virus (rVV) encoding Melan-A(27-35), gp100(280-288), and tyrosinase(1-9) HLA-A*201-restricted epitopes together with B7.1 and B7.2 co-stimulatory molecules. rVV was administered in the context of systemic GM-CSF treatment. Boosts were subsequently administered 2 weeks apart with corresponding synthetic nonapeptides and GM-CSF. Two cycles of treatment were administered 2 weeks apart from each other. Specific immune responses were evaluated by quantitative assessment of cytotoxic T-lymphocyte precursor frequency and tetramer staining. By the time the two cycles had been completed, four out of five patients showed significant (greater than threefold) increases in gp100(280-288)-specific and four out of five, in Melan-A(27-35)-specific tetramer staining of CD8+ cells. Frequencies of CTL precursors specific for gp100(280-288), tyrosinase(1-9) and Melan-A(27-35) were also significantly increased in all five, and in four and four of the five patients, respectively, in some cases within 12 days after the first injection of the recombinant vector. Thus, the innovative vector under investigation is able to raise a concurrent and specific cellular immune response against a panel of molecularly defined antigens, thereby increasing the chance of an immune hit against neoplastic cells displaying heterogeneous antigen expression.

Epitopes↗
PubMed2002

Tissue microarray evaluation of Melanoma antigen E (MAGE) tumor-associated antigen expression: potential indications for specific immunotherapy and prognostic relevance in squamous cell lung carcinoma.

OBJECTIVE: To evaluate MAGE tumor-associated antigen (TAA) expression in an extensive panel of normal and neoplastic tissues. SUMMARY BACKGROUND DATA: TAAs of the MAGE family represent targets of active specific immunotherapy. Limited-size studies indicate that they are expressed in normal testis and tumors of different histologies. High-throughput tissue microarray (TMA) technology and MAGE TAA-specific monoclonal antibodies now allow us to comprehensively evaluate their expression in large numbers of tissues and to address clinical correlations. METHODS: A TMA containing 3,520 samples from 197 different tissues and a non-small-cell lung cancer TMA including 301 specimens were stained using the MAGE TAA-specific monoclonal antibody 57B. For patients with squamous cell carcinoma of the lung, the dichotomous result (positive vs. negative) of MAGE TAA staining was used as a predictor variable along with other covariates in proportional hazard regression analysis of tumor-specific survival. RESULTS: MAGE TAAs are expressed with frequencies ranging between 22.7% (larynx) and 50% of cases (lung) in squamous cell carcinomas from different anatomic areas and in large cell carcinomas of the lung (37.9%). The authors provide here the first description of MAGE TAA expression in basalioma (48.1%). To investigate the clinical significance of MAGE expression in a frequently positive tumor type, a non-small-cell lung cancer, TMA was then studied. In this TMA 43.2% of tumors were 57B positive. In patients with squamous cell carcinoma, MAGE TAA positivity was significantly correlated with a shorter tumor-specific survival in the proportional hazard regression analysis model. CONCLUSIONS: These data suggest novel potential therapeutic indications in different types of cancers. In lung squamous cell carcinoma, the significant association of MAGE TAA expression with poor prognosis suggests that patients with 57B-positive tumors may benefit from early, specific immunotherapy procedures.

Adult↗